Gain of protein function causes many losses

By Ruth SoRelle, M.P.H.

People with neurodegenerative diseases lose. They lose precious brain cells. That leads to the loss of the ability to walk, to talk, to feed themselves, to put on their own clothes. Eventually, they lose their lives.

In the case of a devastating disorder called spinocerebellar ataxia type 1 (SCA1), this loss occurs because of a gain – the gain of protein function that occurs with the 40 or more repeats of three nucleotides or parts of the genetic alphabet that code for an amino acid called glutamine.

Researchers at Baylor College of Medicine and the University of Minnesota in Minneapolis, in a report in the current issue of the journal Nature, unraveled the secret behind the mutated protein's toxic effects. The finding in SCA1 also has implications for other polyglutamine diseases such as Huntington's disease and other ataxias and may play a part in more common disorders such as Alzheimer's and Parkinson's diseases.

Crowded nucleus

Think of the nucleus or "brain center" of the cell as a crowded neighborhood. It functions because its resident proteins bump into one another frequently, setting off activities that keep the cell alive. However, if a protein becomes cliquish, associating mainly with one other protein and leaving others out, it becomes toxic.

That is what the researchers found happening with ataxin1, the mutated form of the protein associated with SCA1. It is more likely to form a protein interaction with some proteins like RNA-binding motif protein 17 (RBM17) than another like Capicua (CIC). As more and more ataxin1 hangs out with RBM17, there is a gain in functions performed by the ataxin-1/RBM17 pair at the expense of ataxin-1/CIC causing loss of function of the latter.

"The nucleus (of the cell) is very crowded," said Huda Y. Zoghbi, M.D., professor of molecular and human genetics, pediatrics, neurology and neuroscience at BCM and senior author of the study. In a crowded environment, every interaction is critical and affects other proteins in the neighborhood.

Protein interaction

"More interaction with RBM17 means that there is less time to interact with other proteins," said Zoghbi, also a Howard Hughes Medical Institute investigator.

However, the multitude of repeats in the mutated form of ataxin1 is not enough to cause disease.

"In the case of ataxin-1, a particular amino acid (serine 776) gets phosphorylated, permitting specific interactions," said Harry Orr, Ph.D., director of the Institute of Human Genetics at the University of Minnesota and another senior author. Because phosphorylation is usually reversible, interactions that require phosphorylation of ataxin-1 at serine 776 can occur transiently (on and off) depending on whether the amino acid is phosphorylated or not.

The interaction between ataxin-1/RBM17 seems to be one such interaction. When the glutamine tract expands in ataxin-1, however, the RBM17/ataxin-1 interaction becomes "on" most of the time, mimicking a continuous phosphorylation state.

"We are beginning to get the idea that the normal function of a protein is important in the disease process," Orr said. Understanding that this serine 776 residue is important in mediating interactions and causing the disease gives researchers a target for developing therapies that might interfere with phosphorylation, rendering the mutant protein less or even non-toxic.

Gain and loss

Janghoo Lim, M.D., first author of the report and a postdoctoral fellow in the department of molecular and human genetics at BCM, said that balance of protein interactions is critical to healthy neurons. A gain in some interactions and therefore functions is the major cause of this disease, but the loss of some normal functions when the protein loses association with other partners is also involved.

"We think that this may apply not only to SCA1 but to other neurodegenerative diseases as well," he said. Among those are Alzheimer's and Parkinson's diseases, for which the underlying mechanisms are still poorly understood and where a better understanding of the neighborhoods and protein partnerships is needed.

Others who took part in this research include Juan Crespo-Barreto, Paymaan Jafar-Nejad, Aaron B. Bowman and Ronald Richman, all of BCM, and David E. Hill of the Dana-Farber Cancer Institute in Boston.

Funding for this research came from the National Institutes of Health, the BCM Mental Retardation Developmental Disorder Research Center, the Ellison Foundation and the W. M. Keck Foundation.

The report can be found at www.nature.com.